针对环素A的PROTAC可以控制病毒诱导的细胞因子风暴
Heqiao Li1,2,3, Wenxian Yang1,2, Huizi Li2,3
1Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China.
iScience
|August 28, 2023
概括
新的蛋白质分解向嵌合体 (PROTACs) 降解环素A (CypA),减少病毒感染期间的有害炎症. 这种方法为治疗严重的细胞因子风暴和急性呼吸困扰综合征提供了有希望的策略.
科学领域:
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
- 病毒学 病毒学
背景情况:
- 细胞因子风暴,标志着高水平的细胞因子和炎症,是病毒感染的危险并发症,如B型流感病毒 (IBV),可能导致急性呼吸困扰综合征.
- 现有的抗病毒治疗方法不足以控制这些严重的炎症反应.
- 环素A (CypA) 被确定为细胞因子生产的关键调节剂,为减轻细胞因子风暴提供了潜在的治疗标.
研究的目的:
- 设计和评估能够降解环素A (CypA) 的蛋白解向仿真体 (PROTAC).
- 调查针对CypA的PROTACs在控制病毒诱导的炎症反应和改善IBV感染小鼠模型的结果方面的疗效.
主要方法:
- 设计了三个新型的PROTAC,专门针对CypA.
- 在细胞系和小鼠器官中评估PROTAC诱导的CypA泛化和降解.
- 评估PROTAC对IBV感染的A549细胞中NF-κB信号通路和促炎细胞因子产生的影响.
- 分析Comp-K (一种针对CypA的PROTAC) 对IBV感染小鼠的细胞因子水平,肺损伤和生存的影响.
主要成果:
- 设计的PROTACs在细胞和动物模型中成功诱导了CypA降解.
- 在IBV感染期间,PROTAC介导的CypA枯竭抑制了P65酸化和NF-κB驱动的炎症前的细胞因子产生.
- 在IBV感染小鼠中,Comp-K治疗显著降低了支气管洗液中的促炎细胞因子,缓解了肺损伤,并改善了生存率.
结论:
- 针对CypA的PROTACs代表了管理病毒诱导的细胞因子风暴的新治疗策略.
- 降解CypA有效地减轻了过度炎症,并改善了疾病的严重程度.
- 这些准CypA的PROTAC显示出潜在的候选人来控制细胞因子风暴和相关并发症.
相关概念视频
Cytotoxic T Cells-mediated Immune Response
963
Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
963
Immune Response Against Viral Pathogens
824
The immune system's response to viral infections is a complex and coordinated process involving natural killer (NK) cells, T cell-mediated responses, and antibody-mediated responses.
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
824
The JAK-STAT Signaling Pathway
9.0K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
9.0K
GPCRs Regulate Adenylyl Cylase Activity
5.7K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.7K
Tumor Immunotherapy
555
Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
555


